The mechanisms involved in defective immune function in HIV infection are not clear. We have proposed that altered regulation of cellular factors in monocytes by HIV infection may contribute to defective immune response in HIV disease. We have demonstrated that reduced capacity by HIV-infected monocytes to stimulate or present antigen to CD4+ T-cells was mediated by cellular factors associated with the cell membranes on the surface of HIV-infected monocytes, and not by the soluble factors secreted by infected cells. Reduced T-cell stimulation induced by HIV-infected monocytes was related to down-modulation of CD4 expression on helper T-cells, and appeared to be mediated by productively infected monocytes. Exposure of CD4+ T-cells, that had been in culture with HIV-infected monocytes, to uninfected monocytes partially restored impaired T-cell stimulation, suggesting that altered ability of HIV-infected monocytes to stimulate CD4+ T-cells to be mediated by membrane-associated factors. Future studies will focus on the identification of these factors on the surface of HIV-infected cells. The identification of HIV-induced cellular factors may provide novel surrogate markers for the detection of HIV-infected cells. To further gain insights into HIV pathogenesis, we have examined cellular pathways in HIV replication which involve the activation of NF-kB in HIV-infected cells. We have shown that treatment of HIV-infected monocytes with inhibitors of protein tyrosine phosphatase blocked NF-kB activity, and abolished HIV replication and HIV-associated cytopathic effects in monocytes. We are currently testing the efficacy of NF-kB inhibitors derived from natural products which may prove useful as potent anti-HIV drugs with no known side effects.